Thrombin Upregulates PAI-1 and Mesothelial–Mesenchymal Transition Through PAR-1 and Contributes to Tuberculous Pleural Fibrosis

International Journal of Molecular Sciences

Wei-Lin Chen¹  Cheng-Ying Hsieh²  Joen-Rong Sheu²  Chih-Hao Yang²  Chi-Li Chung³  Jie-Heng Tsai⁴ 

[1]Department of Nursing, Mackay Junior College of Medicine, Nursing, and Management, Taipei 112, Taiwan

[2]Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan

[3]Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 110, Taiwan

[4]School of Nutrition and Health Sciences, College of Public Health and Nutrition, Taipei Medical University, Taipei 110, Taiwan

关键词: mesothelial–mesenchymal transition;    plasminogen activator inhibitor-1;    pleural fibrosis;    pleural mesothelial cell;    residual pleura thickening;    thrombin;    tuberculous pleural effusion;    tuberculous pleural fibrosis;   

DOI  :  10.3390/ijms20205076

来源: DOAJ

【 摘 要 】

Thrombin is an essential procoagulant and profibrotic mediator. However, its implication in tuberculous pleural effusion (TBPE) remains unknown. The effusion thrombin and plasminogen activator inhibitor-1 (PAI-1) levels were measured among transudative pleural effusion (TPE, n = 22) and TBPE (n = 24) patients. Pleural fibrosis, identified as radiological residual pleural thickening (RPT) and shadowing, was measured at 12-month follow-up. Moreover, in vivo and in vitro effects of thrombin on PAI-1 expression and mesothelial−mesenchymal transition (MMT) were assessed. We demonstrated the effusion thrombin levels were significantly higher in TBPE than TPE, especially greater in TBPE patients with RPT > 10mm than those without, and correlated positively with PAI-1 and pleural fibrosis area. In carbon black/bleomycin-treated mice, knockdown of protease-activated receptor-1 (PAR-1) markedly downregulated α-smooth muscle actin (α-SMA) and fibronectin, and attenuated pleural fibrosis. In pleural mesothelial cells (PMCs), thrombin concentration-dependently increased PAI-1, α-SMA, and collagen I expression. Specifically, Mycobacterium tuberculosis H37Ra (MTBRa) induced thrombin production by PMCs via upregulating tissue factor and prothrombin, and PAR-1 silencing considerably abrogated MTBRa−stimulated PAI-1 expression and MMT. Consistently, prothrombin/PAR-1 expression was evident in the pleural mesothelium of TBPE patients. Conclusively, thrombin upregulates PAI-1 and MMT and may contribute to tuberculous pleural fibrosis. Thrombin/PAR-1 inhibition may confer potential therapy for pleural fibrosis.

【 授权许可】

Unknown